The statements in this section merely provide background information related to the present disclosure and should not be construed as constituting prior art.
The field of coronary angioplasty and stenting has made significant progress in treatment of coronary heart disease through at least three generations of product technology. However, each generational advancement has been accompanied by new challenges. Balloon angioplasty therapy improved acute luminal flow, but vessel recoil and remodeling resulted in high restenosis rates. Bare metal stenting eliminated vessel recoil and minimized abrupt closure events, but restenosis rates were still high due to stent mechanical injury and resulting smooth muscle cell (SMC) migration and proliferation into the lumen.
The current standard of care for treating most de novo coronary lesions is the implantation of a permanent implant known as a drug eluting stent (“DES”). The DES is a third generation angioplasty device for treating coronary stenosis, with significantly lower re-intervention rates than either bare metal stents or balloon angioplasty. This generation of technology is a permanent implant, typically including a high strength and high radio-opacity metal such as cobalt chrome or platinum-enriched stainless steel, coated with a formulation of an anti-proliferative drug in a controlled release polymer.
The next generation of technology is a fully absorbable DES, i.e., the entire mechanical scaffolding (stent) and the drug formulation is broken down in the body and absorbed. The working hypothesis is that any permanent foreign body at the site can prolong inflammation and delay healing and restoration to its native state.
Drug eluting stents cut the retreatment rate significantly by addressing the SMC proliferation with a pharmaceutical agent, but also was accompanied by a “new” complication, late stent thrombosis (LST) and the accompanying extended use of anti-coagulants. LST is believed to result from this delayed healing, and is associated with mortality rates of 30-50%. The apparent factors driving LST appear to be the loss of vaso-motion and delayed healing of a functional endothelium.
Fully absorbable DES have been based on either absorbable polymer technology, such as the well-known PLGA family, or on reactive metals such as magnesium, that readily convert to metallic oxides and organo-metallics in vivo. The magnesium-based approach offers advantages in expandability and radial strength relative to the polymer approaches; however the alloys and manufacturing methods previously used have resulted in stent designs of insufficient ductility to withstand deployment and normal deformations within human arteries.
In particular, attempts to use magnesium and its alloys as a temporary implant biomaterial in cardiovascular stents have been hindered by poor control over the rate and uniformity of the metal's degradation (metallic corrosion rate), fragmentation, and absorption processes in local tissue. Previous attempts at controlling degradation or corrosion rate have focused on alloying with rare earth and other heavy metal elements of unknown biocompatibility, yielding slower corrosion rates but unproven benefits in clinical performance.
Although these approaches have merit for non-medical applications such as commercial or aerospace castings, they are sub-optimal for an absorbable implant grade material that will eventually be fully metabolized by the host tissue, releasing alloying elements of unknown biocompatibility.
It is known that certain metallic impurities in magnesium alloys can rapidly increase its corrosion rate in the presence of physiologic fluids containing chlorides (saline). Most notably are metals such as Fe or Cu, which can form a second phase with dissimilar electronegativities to the magnesium alloy, creating a micro-galvanic cell with vastly increased corrosion rates at the interface. Accordingly, it is common practice in the industry to limit these impurities to low levels (Fe for example to less than 150 ppm), or to alloy with other elements that form complexes with any free Fe to minimize the potential of the micro-galvanic corrosion. However for an absorbable implant grade alloy, these additional elements pose new toxicity concerns.
Furthermore, conventional approaches for corrosion control of magnesium alloys have focused solely on preventing the initial mechanical failure of the given article by retarding the degradation process either by a surface passivation layer, or by changing the local corrosion potential of the alloy. Consideration has not been given to controlling the process of fragmentation, disintegration and absorption following initial mechanical failure. For many implant applications, the timing and nature of the full degradation process, starting with the as-implanted metal article to the final clearance of the alloy mass and its degradants from the anatomical site, is critical for the performance of the medical device.
One such implant application is absorbable metal stents for vascular or luminal scaffolding, such as stents for treatment of coronary artery disease. In this application, the stents provide a temporary scaffolding through the healing process related to the local injury caused by the high pressure angioplasty balloon used to open the stenosed or partially blocked artery. The metal scaffold is required only for a period of days to weeks to prevent abrupt closure of the vessel from spasm, minimize elastic recoil, and as a substrate to deliver a controlled release drug-polymer formulation to the site of injury. After this period, any remnant of the alloy or its degradants is a liability, since it can act as a foreign body prolonging an inflammatory response and delay healing. Furthermore, if the stent remnants remain present in the lumen in solid form through the period of extracellular matrix deposition and scar formation, then the stent remnants themselves become a source of lumen obstruction and participate in a new form of restenosis unknown to conventional permanent stents.